Halogen acyl derivatives of 4,4&#39;-diaminodiphenyl sulphone and process of preparing them



Patented July 6, 1943 HALOGEN ACYL' DERIVATIVES. or 4,4'-DI-l AMINODIPHENYL SULPHONE AND PROC- ESS or PREPARING THEM Horace A. Simple and Arthur M. Van Arendonk, Indianapolis, -Ind., assignors to Eli Lilly and Company, Indianapolis, Ind., a corporation of Indiana No Drawing. Application December 1, 1941,

Serial No. 421,238

a omens. (o1. zoo-397.6)

This application is a continuation in part of applicants copending application, Serial No. 361,585, filed October 17, 1940.

This invention relates to halogen acyl derivatives of chemotherapeutic agents and processes of preparing them.

Many of the compounds of this invention are particularly efficacious in combating. streptococcal infections. For example, a dose of 4,4-di- (trichloroacetylamino)diphenyl sulphone is at least as effective as 4,4-diaminodiphenyl sulphone when administered orally or introperitoneally to white mice in combating streptococcic infections. In addition, the compounds of this invention are markedly less toxiothan the par-' ent substances from which they are derived.

The compositions of this invention may be represented by the following formula:

' Rn Throughout the description of this invention R1, R2, and R3 have the same meaning as heretofore defined. The substituents R1, R1 in Formulas 1 and 2 represent identical halogens.

The compositions of thlSfiIlVeIltlOll are pre:

pared by the following method:

One molecular equivalent of a substituted acetyl halide having the following formula:

(3) it t R1( X 1's,

in w hich X represents chlorine or bromine, is reacted with one or preferably two molecular equivalents of a 4-amino-4'-R4-aminodiphenyl sulphone, having the following formula:

in. which R4 isa member of the class consisting of hydrogen, acetyl, propionyl and butyryl.

The 4-amino 4-R4-aminodiphenyl sulphone is dissolved or suspended in a suitable solvent, preferably miscible with water, such as dioxane, and the substituted acetyl chloride is added .to

a the solution or suspension. Other solvents which are not miscible with water, such as ethyl acetate, may be used, The mixture is agitated, as by means of stirring, and permitted to stand for approximately one hour, Within which time the reaction is completed and the desired compound formed. An excess of water is then added together with sufficient mineral acid, such a hydrochloric acid, to help keep in'solution the un reacted or unacylated 4amino-4-R4-aminodiphenyl sulphone. Tne'resulting suspension is cooled until the bulk of the newly prepared-material has solidified. The desired product is separated frorn the supernatant liquid by any suitable means, such as filtration. Thisprecipitate may be purified by recrystallization from a solvent, such as methyl alcohol, dioxane, or glacial acetic acid. The reaction which takes place when R4 is acetyl, propionyl or butyryl may be represented by the following equation:

The reaction whi chtakes place when R4 is hydrogen may be representedv by the following equation:

It is observed that the one molecular equivalent cf the amino base acts to neutralize the hydroha gen acid which is formed. The amino base is soluble in acid, whereas the halogen acyl derivative is relatively insoluble in acid. For this reason, it is desirable to add a small quantity of a mineral acid, such as hydrochloric acid, to the reaction mixture after the reaction has been completed and the mixture has been diluted in solution in order to retain the unreacted or unacylated 4-amino-4 RA-aminodiphenyl sulphone in solution.

In certain cases, instead of using two molecular equivalents of the 4-amino-4 its-aminodiphenyl sulphone, one molecular equivalent of the 4- amino-4'-R4-aminodiphenyl sulphone and another base, such as pyridine, sodium carbonate or sodium bicarbonate, may be employed. In using an inorganic base, such as sodium bicarbonate, which is substantially insoluble in the organic solvents employed, an aqueous phase is required for the efficient practice of the method.

Some examples of the preparation of derivatives of this invention are as follows:

EXAMPLE 1.The preparation of 4-tri r0m0acetylamino-4-acetylaminodiphenyl sulphone 5.8 g. (about 0.02 mol) of -4-amino-4'-acetylaminodiphenyl sulphone are dissolved in about 100 cc. of dioxane and to this solution are added, with stirring 3.6 g. (about 0.01 mol) of tribromoacetyl bromide. The mixture is agitated for a period of fifteen minutes and is allowed to stand at room temperature for about one hour within which time 4-tribromoacetylamino-4-acetylaminodiphenyl sulphone is produced. The mixtur is then diluted with about 300 cc. of water, to which about 30 cc. of concentrated hydrochloric acid (sp. gr. 1.2) are added. The 4-tribromoacetyl-4'- aminodiphenyl sulphone separatesout as an oil or crystalline solid. To secure a larger yield-and facilitate crystallization, the mixture .is chilled to less than 10 C. for about two or three hours. The solid precipitate is filtered off. To purify the product, the precipitate is dissolved in boiling dioxane or other suitable solvent. The hot solution is diluted slightly with water to incipient precipitation and is cooled. The solid material which separates is 4-tribromoacetylamino-4'-acetylaminodiphenyl sulphone which melts at about 254255 C., uncorrected. The reaction which takes place may be represented by the following equation:

and 4-tribromoacetylamino-4'-butyrylaminodiphenyl sulphone Instead of using 4-amino-4-acetylaminodiphenyl sulphone, as outlined in Example 1, an equivalent amount of 4-amino-4-propionylaminodiphenyl sulphone or 4-amino-4'-butyrylaminodiphenyl sulphone may be used to produce respectively 4 tribromoacetylamino-4'-propionyl aminodiphenyl sulphone or l-tribromoacetylamlno-'-butyrylaminodiphenyl sulphone.

The 4 amino-4-propionylaminodiphenyl sulphone employed to prepare 4-tribromoacetylamino-4'-propionylaminodiphenyl sulphone is a new compound and is prepared as follows:

To 25 g. (about 0.1 mol) of 4,4-diaminodiphenyl sulphone dissolved in 200 cc. of boiling dioxane .are added 13 g. (about 0.1 mol) of propionic anhydride. The solution is boiled for several minutes, during which time the desired product is formed, and then allowed to cool to room temperature. The solution is then poured into 1.5 liters of water containing cc. of concentrated hydrochloric acid (sp. gr. 1.2) and i then allowed to stand for one hour, after which time the insoluble 4,4'-dipropionylaminodiphenyl sul- 'phone is removed by filtration. The filtrate is partially neutralized with ammonium hydroxide solution until a slight cloudiness appears. It is then chilled to below 5 C. for preferably not less than eight hours. The precipitate which forms consists of the desired 4-amino-4'-propionylaminodiphenyl sulphone with some unchanged 4,4-diaminodiphenyl sulphone. This precipitate is dissolved in a minimum amount of boiling methyl alcohol and then cooled to preferably slightly belowv 0 C. The precipitate is filtered off and recrystallized once or twice from methyl alcohol. The 4-amino-4-propionylaminodiphenyl sulphone melts at about 200-201 C., uncorrected, and may be represented by the following formula:

EXAMPLE 3.The preparation of 4-trichloroacetylaminol'-acetylaminodiphenyl sulphone Instead of using tribomoacetyl bromide, as outlined in Example 1, an equivalent amount of trichloroacetyl chloride may be used to produce 4- trichloroacetylamino -4'- acetylaminodiphenyl sulphone. The 4-trichloroacetylamino-4'-acetylaminodiphenyl-sulphone has a melting point of about 268-269 C., uncorrected, and may be represented by the following formula:

OH H

EXAMPLE 4.-The preparation of 4-trichloro acetylamz'no -4'- propionylaminodz'phenyl-sulphone and 4-trichloroacetyZamino-el'-butyrylaminodiphenyl sulphone 1 Instead of using 4-amino-4-acetylaminodiphenyl sulphone, as outlined in Example 1, an equivalent amount of 4-amino 4-propionylaminodiphenyl sulphone and 4-amino-4-butyrylaminodiphenyl sulphone is reacted with the required amount of trichloroacetyl chloride to produce respectively 4-trichloroacetylamino-4'-propionylaminodiphenyl sulphone and 'i-trichldroacetylaminoi-butyrylaminodiphenyl*- sulphone.

EXAMPLE 5.--The preparation of dibromoacetylamino-4 -acetylaminodiphenyl 'salphone separates out as an oil or crystalline solid. To

secure a larger yield and facilitate crystallization, the mixture is chilled to less than 10 C. for about two or three hours. The solid precipitate is filtered off. To purify the product, the precipitate is dissolved in boiling dioxane or other suitable solvent. The hot solution is diluted slightly with water to incipient precipitation and is cooled. The solid material which separates is 4 dibromoacetylamino -4'- acetylaminodiphenyl sulphone and is represented by the following formula:

(10) Br H EXAMPLE 6.The preparation of 4-dibromoacet'Jlamino-4'-propionylaminodiphenyl sulphone and 4-dibromoacetylamino-4-bntyrylaminodiphenyl sulphone Instead of using 4-amino-4-acetylaminodiphenyl sulphone, as described in Example 5, an equivalent amount of 4-amino-4'-propionylaminodiphenyl sulphone or 4-amino-4'-butyrylaminodiphenyl sulphone may be used to produce respectively 4-dibromoacetylamino-4'-propionylaminodiphenyl sulphone or 4-dibromoacetylamino-4'-butyrylaminodiphenyl sulphone.

EXAMPLE 7.The preparation of 4-dichloracetylamino-4'-acetylaminodiphenyl sulphone Instead of using dibromoacetyl bromide, as outlined in Example 5, an equivalent amount of dichloroacetyl chloride may be used to produce 4 dichloroacetylamino -4'- acetylaminodiphenyl sulphone.

EXAMPLE 8.The preparation of 4-dichloracetyZamino-4-propionylaminodiphenyl sulphone and 4-dichloroacetylamino-4'-butyrylaminodiphenyl sulphone Instead of using 4-amino-4-acetylaminodiphenyl sulphone, as outlined in Example 5, an equivalent amount of 4-amino-4'-propionylaminodiphenyl sulphone and 4-amino-4'-butyrylaminodiphenyl sulphone is reacted with the required amount of dichloroacetyl chloride to produce respectively 4-dichloroacetylamino-4-propionylaminodiphenyl sulphone and 4-dichloroacetylamino-4-butyrylaminodiphenyl sulphone.

EXAMPLE 9.-The preparation of 4,4-di(tribr0- moacetylamino) diphenyl sulphone To 5 g. (about 0.02 mol) of diaminodiphenyl sulphone dissolved in 100 cc. of dioxane are added '72 (about 0.02 mol) of tribromoacetyl'bromide. The mixture is agitated and allowed to stand for one hour, within which time the 4,4-di(tribromoacetylamino di-phenyl sulphone is produced. The mixture is then diluted with 300 cc. of water to which about 50 cc. of concentrated hydrochloric acid, or hydrobromicacid, are added and a precipitate, which is the desired product, is formed. The mixture is chilled, for a period or two to three hours and the precipitate which formed is filtered. The precipitate is dissolved in a minimum amount of boiling dioxane and placed in a refrigerator and allowed to cool, whereupon the purified 4,4'-di(tribromoacetylamino)diphenyl sulphone precipitates. This compound may be represented by the following formula:

W? i we Br 0 Br EXAMPLE 10.--The preparation of 4,4'-di(trichloroacetylamino) diphenyl sulphone EXAMPLE 11.-The preparation of 4,4'-di(dichloroacetylamino) diphenyl sulphone To 5 g. (about 0.02 mol) of 4,4'-diamin0diphenyl sulphone dissolved in cc. dioxane are added 2.9 g. (about 0.02 mol) of dichloroacetyl chloride. The mixture is allowed to stand for one hour, within which time the desired product is formed, and is then diluted with 300 cc. of water to which 30 cc. of concentrated hydrochloric acid are added. The resulting mixture is chilled to a temperature of approximately 5 C. to secure the maximum amount of precipitation. The precipitate, which is the desired product, is filtered 01f. To purify this precipitate, it is dissolved in boiling dioxane, diluted slightly with water to incipient precipitation and cooled to approximately 0 C. The 4,4'-di(dichloroacetylamino)diphenyl sulphone is filtered off. It decomposes with foaming at about 100 C., uncorrected, and may be represented by the following formula:

03 til i i i i EXAMPLE 12.--The preparation of 4,4'-di(dibromoacetylamino) -diphenyl sulphone Instead of using dichloroacetyl chloride, as outlined in Example 11, an equivalent amount of dibromoacetyl bromide may be used to produce 4,4-di(dibromoacetylamino)diphenyl sulphone.

What is claimed is:

y the y the 1. A compound which is represented b 3. A composition which is represented b following formula: following formula:

2. A compound which is represented by th in which the two Rs represent like radicals sefollowing formula: selected from the class which consists of tri- Cl 0 H O chloroacetyl, dlchloroacetyl, tribromoacetyl and CI 5 (|Jl 1 g 10 dibromoacetyl radicals.

| OTTO HORACE A. SHONLE. C1 0 ARTHUR M. VAN ARENDONK.

CERTIFICATE OF CORRECTION. Patent No. 2,5 5,575- July 6, 19b5,-

HORACE A. SHONLE, ET AL.

ereb'y certified that error appears in the printed specification It is h of the above numbered patent requiring correction as follows: Page 1; sec- 0nd column, line 11+, for reacted or unacylated ll-amino-h-R -aminodb" read --reacted or unacylated LL-amino-Lp -R and that the said Letters Patent should be read with this correction therein that the same may conform to the record of the case in the Patent Office.

Signed and sealed this 10th day of August, A. D. 19LL5.

Henry Van Arsdale,

(Seal) Acting Commissioner of Patents 

